Some of the pathogenesis of disease in diabetes mellitus is associated with the enzyme aldose reductase. Diabetic cataract formation results following a complex interaction between aldose reductase, its substrates, co-enzyme, products and effectors. Since aldose reductase catalyzes the first step in the sorbitol pathway, it is quite reasonable to expect to find that multiple controls and not just elevated sugar levels are involved in regulating this process. Secondly, our studies with pure aldose reveal kinetic properties characteristic of substrate activation of homotrophic cooperativity manifested by increases in substrate-enzymes affinity. Such curves are characteristic of substrate activation, homotrophic co-operativity and an increase in enzyme affinity as reflected by the changed Km values. To this end, we plan to explore some of the yet unclear regulatory processes that could serve as important control mechanisms for aldose reductase and subsequently cataracts in galactose fed and diabetic rats. Rapid decreases in the levels of the coenzyme NADPH are observed in both groups of experimental rats in the first two days and well before cataract formation can be detected by physical examination. We propose to look for changes in the aldose reductase protein that could account for its sudden activation "In Vivo." We shall look for covalent modification of the enzyme protein and also for activators that may be compartmentalized in lens during these early phases of cataract formation of galactose feeding and diabetes.